Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning

doi:10.1016/S0306-4522(00)00437-1

Neuroscience

Volume 101, Issue 4, 30 November 2000, Pages 921-930

https://doi.org/10.1016/S0306-4522(00)00437-1 Get rights and content

Abstract

Latent inhibition describes a process by which pre-exposure of a stimulus without consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that latent inhibition in rats is impaired by increased dopamine function and potentiated by reduced dopamine function. Previous evidence has suggested that these effects are modulated via the meso-accumbens dopamine projections. We have now undertaken three experiments to examine this issue directly, especially in the light of one study in which latent inhibition was reported to be unaffected by direct injection of amphetamine into the accumbens. Latent inhibition was studied using the effect of pre-exposure of a tone stimulus on the subsequent formation of a conditioned emotional response to the tone. 6-Hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens resulted in potentiation of latent inhibition. Bilateral local injections of the dopamine antagonist haloperidol into the nucleus accumbens (0.5 μg/side) before conditioning also potentiated latent inhibition. Moreover, such injections were able to reverse the disruptive effect of systemic amphetamine (1 mg/kg, i.p.) on latent inhibition. Bilateral local injection of amphetamine (5 μg/side) into the nucleus accumbens before conditioning was able to disrupt latent inhibition, provided that it was preceded by a systemic injection of amphetamine (1 mg/kg) 24 h earlier.

We conclude that the attenuation of latent inhibition by increased dopamine function in the nucleus accumbens is brought about by impulse-dependent release of the neurotransmitter ocurring at the time of conditioning. The previously reported failure to disrupt latent inhibition with intra-accumbens amphetamine is probably due to impulse-independent release of dopamine. The implications of these conclusions for theories linking disrupted latent inhibition to the attentional deficits in schizophrenia, and to the dopamine theory of this disorder, are discussed.

Section snippets

Subjects and behavioural apparatus

All experiments were performed on male Sprague–Dawley rats (250–275 g on arrival), supplied by B & K Universal (Hull, UK). Animals were housed four to a cage, with food provided ad libitum, under controlled temperature, lighting (06.00–20.00) and humidity. Experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act, 1986, under appropriate project and personal licences. All efforts were made to minimize the number of animals used and their suffering.

Behavioural

Neurochemical

As shown in Table 2, local injection of 6-OHDA resulted in a marked and significant depletion of DA in the NAcc (>75%), in contrast to the caudate (<15%). There was also a modest fall in DA levels in the amygdala (c. 30%). The latter two reductions were not statistically significant.

Behavioural

The analysis of the A times revealed no significant effects of either Treatment or Pre-exposure on baseline lick rates; mean A times ranged from 2.1 to 2.9 s. As expected with 10 pre-exposures (see Introduction and

Discussion

Reduction of accumbal DA function by either neurotoxic lesion (experiment 1) or by local administration of haloperidol (experiment 2) gave rise to potentiated LI. It is unlikely that the behavioural effect is due to the spread of these agents to neighbouring dopaminergically innervated areas of the dorsal striatum or amygdala. The former is unlikely because the lesion caused a major depletion of DA in the NAcc, but minimal depletion in the dorsal striatum. Furthermore, a replicate

Conclusion

Overall, we interpret our present and previous findings as supporting the view that, in the rat, modulation of impulse-dependent DA activity in the NAcc at the time of conditioning alters the relative impact of information previously acquired during pre-exposure, i.e. learning that the to-be-conditioned stimulus is familiar. Increased DA transmission in the NAcc in association with presentation of the stimulus reduces the impact of such prior experience, while reduced DA transmission in the

Acknowledgements

We thank the Medical Research Council (UK) and the Wellcome Trust for project grant support. M.H.J. was a member of the MRC external scientific staff and P.M.M. was the holder of an EU research fellowship. We thank Chris Naylor for assistance with the locomotor and stereotypy assessments.

References (51)

M.P. Brazell et al.
Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate–putamen
Neuropharmacology
(1990)
I. Creese et al.
Blockage of amphetamine-induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine
Brain Res.
(1973)
J. Feldon et al.
Latent inhibition is unaffected by direct dopamine agonists
Pharmac. Biochem. Behav.
(1991)
J.A. Gray et al.
Latent inhibition: the nucleus accumbens connection revisited
Behav. Brain Res.
(1997)
N.S. Gray et al.
Latent inhibition in drug naive schizophrenics; relationship to duration of illness and dopamine D2 binding using SPET
Schizophrenia Res.
(1995)
G. Grigoryan et al.
6-OHDA lesions of the nucleus accumbens accentuate memory deficits in animals with lesions to the forebrain cholinergic projection system: effects of nicotine administration on learning and memory in the water maze
Neurobiol. Learn. Mem.
(1996)
A. Imperato et al.
Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats
Eur. J. Pharmac.
(1986)
P.W. Kalivas et al.
Dopamine transmission in the initiation and expression of drug-and stress-induced sensitisation of motor activity
Brain Res. Rev.
(1991)
M. Konstandi et al.
Effects of striatal or accumbens lesions on the amphetamine-induced abolition of latent inhibition
Pharmac. Biochem. Behav.
(1993)
T.E. Robinson et al.
Enduring changes in brain and behaviour produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res. Rev.
(1986)

Cited by (82)

Dopamine-glutamate neuron projections to the nucleus accumbens medial shell and behavioral switching
2019, Neurochemistry International
Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus accumbens (NAc) medial Shell, their distinct anatomical and functional connections, and discuss their role in motivated behavior. We first review rodent studies showing that a subpopulation of DA neurons in the medial ventral tegmental area (VTA) project to the NAc medial Shell. Using a combinatorial strategy, we show that the majority of DA neurons projecting to the NAc Shell express vesicular glutamate transporter 2 (VGLUT2) making them capable of glutamate co-transmission (DA-GLU neurons). In the NAc dorsal medial Shell, all of the DA neuron terminals arise from DA-GLU neurons, while in the lateral NAc Shell, DA neuron terminals arise from both DA-GLU neurons and DA-only neurons, without VGLUT2. DA-GLU neurons make excitatory connections to the three major cells types, spiny projection neurons, fast-spiking interneuron and cholinergic interneurons (ChIs). The strongest DA-GLU neuron excitatory connections are to ChIs. Photostimulation of DA-GLU neuron terminals in the slice drives ChIs to burst fire. Finally, we review studies that address specially the behavioral function of this subpopulation of DA neurons in extinction learning and latent inhibition. Taking into account findings from anatomical and functional connectome studies, we propose that DA-GLU neuron connections to ChIs in the medial Shell play a crucial role in switching behavioral responses under circumstances of altered cue-reinforcer contingencies.
Disruption of latent inhibition by subchronic phencyclidine pretreatment in rats
2019, Behavioural Brain Research
Repeated subchronic treatment with the NMDA-receptor antagonist, phencyclidine, causes behavioural changes in rats, which resemble cognitive and negative symptoms of schizophrenia. However, its effects on behaviours modelling positive symptoms are less clear. This study investigated whether subchronic phencyclidine pretreatment affected latent inhibition: impaired conditioning following repeated preexposure of the to-be-conditioned stimulus.
Female Lister-hooded rats were pretreated with phencyclidine or saline twice/day for 5 days, then remained drug-free for 10 days before latent inhibition testing. Saline pretreated animals showed latent inhibition, as expected. However, phencyclidine pretreated animals showed no latent inhibition: the effect of preexposure was attenuated, with no change in basic learning. Thus subchronic phencyclidine pretreatment does disrupt latent inhibition, and, importantly, this occurs after withdrawal from the drug, implicating changes in brain function enduring well beyond the time that the drug is present in the brain.
In a separate task, discrimination of a novel object was significantly impaired by phencyclidine pretreatment confirming that five days of subchronic pretreatment was sufficient to invoke behavioural impairment previously reported after seven days pretreatment.
Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions
2014, Comptes Rendus - Biologies
Citation Excerpt :
Thus, the timing of drug administration is a critical factor, which still needs to be clarified. Several studies have been done on the timing of drug administration by comparing the effects of dopamine manipulations during the PE phase, the conditioning phase, or both [27,28]. These studies agree that altered LI could be observed only when DA neurotransmission is manipulated during the conditioning phase [28].
Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition.
Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition.
Les lésions néonatales de l’hippocampe ventral chez les rats provoquent des altérations comportementales, comme l’anxiété et la diminution de l’inhibition latente, deux comportements relatifs au phénotype schizophrène. Notre travail avait pour objectif de préciser l’effet facilitateur de l’halopéridol sur l’inhibition latente après son administration en phase de préexposition à la suite d’une lésion néonatale bilatérale de l’hippocampe ventral. Nos résultats montrent que les animaux lésés présentent une diminution significative aussi bien au niveau du nombre de leurs interactions sociales qu’à celui du nombre de billes enterrées. Chez ces animaux, l’activité locomotrice est largement augmentée par rapport aux témoins. Le conditionnement d’évitement a montré que la lésion altère de façon significative l’inhibition latente, qui se trouve diminuée par rapport au témoin. Ce résultat est confirmé par le test d’aversion gustative conditionnée. Cependant, nous avons pu montrer que l’administration d’halopéridol avant chaque session de pré-exposition permet de faciliter l’inhibition latente.
Role of insular cortex D<inf>1</inf> and D<inf>2</inf> dopamine receptors in nicotine self-administration in rats
2013, Behavioural Brain Research
The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1–2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5–2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward.
Paradoxical effects of low dose MDMA on latent inhibition in the rat
2013, Neuropharmacology
Citation Excerpt :
Control rats were injected with the equivalent volume of saline. Drug or control injections were administered 40 min prior to the pre-exposure and conditioning stages of the procedure (Joseph et al., 2000). Thus all rats given MDMA received 2 doses of 6 mg/kg with a 24 h gap between the two doses.
The cognitive effects of MDMA (‘Ecstasy’) are controversial, particularly in the case of acute administration of low doses. Latent inhibition (LI) refers to the reduction in conditioning to a stimulus that has received non-reinforced pre-exposure, an effect typically abolished by amphetamines and enhanced by antipsychotics. LI enhancement has also been shown using the 5-HT reuptake blocker sertraline. In the present study, the effects of MDMA (6 mg/kg, known to increase 5-HT release) were tested using 10 and 40 pre-exposures to produce weak and strong LI in controls, respectively. MDMA (injected twice, prior to pre-exposure and conditioning) significantly enhanced LI in that the effect was clearly demonstrated after only 10 pre-exposures, when it was absent in the saline controls. On its own such a profile of action would be consistent with a procognitive effect of MDMA mediated by increased availability of 5-HT. However, paradoxically the same MDMA treatment reduced LI in the 40 pre-exposures condition. This component of action is likely attributable to MDMA's actions on catecholaminergic systems and is consistent with other evidence of its adverse effects. Moreover, there were small but significant reductions in 5-HT in medial prefrontal cortex (mPFC) and amygdala assayed 7 days post MDMA administration (2 × 6 mg/kg, 24 h apart).
Abnormally rapid reversal learning and reduced response to antipsychotic drugs following ovariectomy in female rats
2012, Psychoneuroendocrinology
Epidemiological and clinical life cycle studies indicate that favorable illness course and better response to antipsychotic drugs (APDs) in women with schizophrenia are positively correlated with estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes a neuroprotective role of estrogen in women vulnerable to schizophrenia. Previously we demonstrated in the rat that low levels of estrogen induced by ovariectomy led to disruption of latent inhibition (LI) reflecting impairment of selective attention, a core deficit of schizophrenia. LI disruption was reversed by 17β-estradiol and the atypical APD clozapine, whereas the typical APD haloperidol was ineffective unless co-administered with 17β-estradiol. Here we aimed to extend these findings by testing ovariectomized rats in another selective attention task, discrimination reversal. Ovariectomy led to a loss of selective attention as manifested in abnormally rapid reversal. The latter was normalized by high dose of 17β-estradiol (150 μg/kg) and clozapine (2.5 mg/kg), but not by haloperidol (0.1 mg/kg) or lower doses of 17β-estradiol (10 and 50 μg/kg). However, co-administration of haloperidol with 17β-estradiol (50 μg/kg) was effective. In sham rats low 17β-estradiol (10 μg/kg) produced rapid reversal, while high 17β-estradiol (150 μg/kg), haloperidol alone, or haloperidol-17β-estradiol combination reduced reversal speed. Clozapine did not affect reversal speed in sham rats. These results strengthen our previous results in suggesting that schizophrenia-like attentional abnormalities as well as reduced response to APDs in female rats are associated with low level of gonadal hormones. In addition, they support the possibility that estrogen may have an antipsychotic-like action in animal models.

View all citing articles on Scopus

^†: Present address: Behavioural Neuroscience Group, School of Psychology, University of Leicester, University Road, Leicester, LE1 7RH, UK.

View full text

Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning

Abstract

Section snippets

Subjects and behavioural apparatus

Neurochemical

Behavioural

Discussion

Conclusion

Acknowledgements

Neuropharmacology

Brain Res.

Pharmac. Biochem. Behav.

Behav. Brain Res.

Schizophrenia Res.

Neurobiol. Learn. Mem.

Eur. J. Pharmac.

Brain Res. Rev.

Pharmac. Biochem. Behav.

Brain Res. Rev.

Brain Res.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Neuroscience

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition

Behav. Pharmac.

Differential performance of acute and chronic schizophrenics in a latent inhibition task

J. nerv. ment. Dis.

Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioural model of clinical drug action

Psychopharmacology

The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm

Psychopharmacology

Integrating schizophrenia

Schizophrenia Bull.

The neuropsychology of schizophrenia

Behav. Brain Sci.

The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia

Behav. Brain Res.

Abolition of latent inhibition in acute, but not chronic, schizophrenics

Neurol. psychiat. Brain Res.

Abolition of latent inhibition by a single 5 mg dose of d-amphetamine in man

Psychopharmacology

Selective hippocampal lesions abolish the contextual specificity of latent inhibition and conditioning

Behav. Neurosci.

Nicotine blocks latent inhibition in rats: evidence for a critical role of increased functional activity at conditioning rather than preexpsoure

Psychopharmacology